GB2163150A

GB2163150A - 3-Aminopropoxyaryl derivatives

Info

Publication number: GB2163150A
Application number: GB08517068A
Authority: GB
Inventors: Richard Berthold; Hans Ott
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1984-07-19
Filing date: 1985-07-05
Publication date: 1986-02-19
Also published as: FR2567885A1; FR2567885B1; IT1200092B; CH665208A5; BE902897A; GB8517068D0; GB2163150B; IT8548373A0

Abstract

The compounds of formula I where R is alkyl disubstituted by aromatic, heteroaromatic and/or cycloaliphatic groups and Ar, B and p have various significances, and physiologically acceptable hydrolyzable derivatives thereof having the hydroxy group in the 2 position of the propoxy side chain in esterified form are indicated for use as cardiotonic, antiarrhythmic, alpha - and beta -adrenoceptor blocking and calcium antagonistic agents.

Description

SPECIFICATION 3-Aminopropoxyaryl derivatives, their preparation and pharmaceutical compositions containing them The present invention relates to 3-aminopropoxyaryl derivatives, their preparation and pharmaceutical compositions containing them.

In accordance with the invention there are provided compounds of formula I

wherein Ar is an aromatic or heteroaromatic group; B is: a group i), ii), iii) or iv) having the following significances:

wherein V and W are hydrogen or together form an additional bond; and Rj is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or phenyl monosubstituted or independently disubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35;

wherein Rj is hydrogen or alkyl of 1 to 4 carbon atoms;

wherein n is 2, 3 or 4, Rk is hydrogen or alkyl of 1 to 4 carbon atoms and R, has the significances indicated above for R; and

wherein m is 2 or 3; p is O or 1; and R is alkyl independently disubstituted by aromatic, hetero-aromatic and/or cycloaliphatic groups; with the proviso that when a) Ar is a group of formula A

wherein either R' is: hydrogen, methyl, hydroxymethyl, carboxyl, alkoxycarbonyl of altogether 2 to 5 carbon atoms, carbamoyl or cyano and R" is: hydrogen or methyl; or R' is: hydroxy and R" is: hydrogen; and additionally b) either p is 1 and B is: agroup i') of formula

wherein Ri is as defined above and V' and W' are hydrogen or, when R' is hydroxy and R" is hydrogen, V' and W' are hydrogen or together form an additional bond; or a ornuu ii) or iii) as defined above; or p is 0 or 1 and B is: a group iv') of formula

then R is other than diphenylalkyl of 13 to 17 carbon atoms or diphenylalkyl of 13 to 17 carbon atoms mono- or independently disubstituted in any of the phenyl rings by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35; and physiologically hydrolyzable derivatives thereof having the hydroxy group in the 2 position of the propoxy side chain in esterified form, hereinafter referred to as "the compounds of the invention".

Physiologically hydrolyzable derivatives are derivatives which under physiological conditions are split to the corresponding compounds having a hydroxy group in the 2 position of the propoxy side chain.

A group of derivatives in esterified form of the compounds of formula I is e.g. the compounds of formula E,

wherein Ar, B, p and R are as defined above; and R, is alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms, phenyl or phenylalkyl of 7 to 12 carbon atoms monosubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, or mono-or independently disubstituted in the phenyl ring by halogen of atomic number of from 9 to 35, or mono- or independently di- or independently trisubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms.

Preferred are the compounds wherein the hydroxy group in the 2 position of the propoxy side chain is in unesterified form.

When the compounds of the invention may be represented in tautomeric structure such tautomeric forms are also part of the invention. For example, when Ar is an indole group substituted by hydroxy in the 2-position, the oxindole form is also included.

Compounds structurally similar to the compounds of the present invention are described in e.g. European Patent Specifications No. 25 111 and U.K. Patent Specification No. 2 091 262 and their equivalents.

These disclosures have been excluded from the scope of the present invention by the proviso. The disclosures do neither specifically disclose nor suggest the compounds of the present invention.

Ar may be monocyclic or polycyclic, it may e.g. consist of two fused rings. It preferably is polycyclic.

When it is polycyclic and heteroaromatic it preferably is a fused, fully unsaturated ring system with at least one nitrogen heteroatom. Ar may e.g. be an indol, oxindol, 2,1,3-benzoxadiazol, benzimidazol, ben zimidazol-2-on, chinolin-2-on, 3,4-dihydrochinolin-2-on, carbazol, spiro[cyclohexan-1 ,2'-indan]-1 '-on, phenyl, pyridyl or pyridinon group.

Ar may be substituted or unsubstituted.

Ar preferably is an indol or oxindol group, especially bound to the propoxy side chain with the 4-position; it especially is 2-cyano-1H-indol-4-yl.

Another preferred group Ar is phenyl.

B preferably is a group iv). When it is a group i), ii) or iii) it preferably is a group i) or ii). V and W preferably are hydrogen. RF, Rj and/or R, preferably are hydrogen or alkyl, especially hydrogen. n preferably is 2. Rk preferably is hydrogen m preferably is 2. When Ri and/or R, are optionally substituted phenyl they are preferably unsubstituted. If they are substituted phenyl the phenyl ring preferably is monosubstituted, especially in the 4-position, or disubstituted, especially in the 3- and 4-positions.

p preferably is 0 when B is a group iv). It preferably is 1 when B is a group i), ii) or iii).

R preferably is alkyl independently disubstituted by at least one aromatic or heteroaromatic group and a further group which may be aromatic, heteroaromatic or cycloaliphatic. When Ar is an indol group then at least one of the two groups in R preferably is other than phenyl. They maybe substituted or unsubstituted.

The two groups substituting the alkylene part in R preferably are bound to the same carbon atom They preferably are attached to the carbon atom in the "-position. For example, diphenylalkyl preferably is diphenylmethyl.

An aromatic group in R preferably is a phenyl group.

A heteroaromatic group in R preferably is pyridinyl, thienyl, furyl, pyrrolyl or imidazolyl, especially thienyl or pyridinyl.

A cycloaliphatic group in R preferably is of 3 to 7 carbon atoms, preferably 5 to 6 carbon atoms, it especially is cyclohexyl.

It may contain heteroatoms, e.g. one oxygen atom or an oxygen and a nitrogen atom in the cycle, such as in tetrahydropyran or morpholine.

When it can be either substituted or unsubstituted a substituent phenyl ring preferably is unsubstituted. When such a phenyl ring is substituted it preferably is monosubstituted. When it is monosubstituted the substituent preferably is in the para position. When it is disubstituted the substituents preferably are in the meta- and para-positions. When it is polysubstituted the substituents preferably are identical.

A preferred group of compounds of the invention is the compounds of formula la,

wherein Ar, is:- phenyl; phenyl monosubstituted by hydroxy, benzyloxy, carboxy, alkoxycarbonyl of altogether 2 to 5 carbon atoms, trifluoromethyl, acetylmethyl, methylsulfonylamino, cyanomethylamino, amino, ace tamido, (1 -hydroxymethyl-cyclohexyl )methyl, (1 -acetoxymethylcyclohexyl)methyl, 1 -d imethylam ino-3-oxo- 1-buten-2-yl or 3-cyano-1,2-dihydro-6-methyl-2-oxopyridin-5-yl; or phenyl disubstituted by: either nitro, amino, hydroxy or benzyloxy; or hydroxy and cyano; or benzyloxy and cyano; or acetyl and [2-meth oxyjethoxy; or cyano and [2-methoxy]ethoxy; or nitro and methyl; - indolyl; indolyl monosubstituted in the 2-position by methyl, hydroxymethyl, carboxyl, alkoxycarbonyl of altogether 2 to 5 carbon atoms, carbamoyl, cyano or acetyl; indolyl monosubstituted in the 3-position by methyl or cyano; indolyl monosubstituted in the 6-position by carboxyl or alkoxycarbonyl of alto gether 2 to 5 carbon atoms; indolyl monosubstituted in the 7-position by fluorine or alkoxyalkyl of 1 to 4 carbon atoms in each of the alkyl and alkoxy moieties thereof; indolyl disubstituted, in the 1-position by alkyl of 1 to 4 carbon atoms, alkoxy-carbonyl of altogether 2 to 5 carbon atoms or alkoxy-carbonylalkyl of altogether 3 to 9 carbon atoms and in the 2-position by cyano, or in the 2- and 3-positions by cyano, or in the 2-position by methyl, hydroxymethyl, carboxyl, alkoxycarbonyl of altogether 2 to 5 carbon atoms, carbamoyl or cyano and in the 3-position by methyl, or in the 2-position by cyano and in the 3-position by dimethylaminomethyl; - oxindolyl or oxindolyl substituted in the 3-position by two methyl groups; - 2, 1,3-benzoxadiazol-4-yl; - benzimidazol-4-yl or 2-trifluoromethylbenzimidazol-4-yl; - 1 ,2-dihydro-2-oxobenzimidazol-4-yl; - [chinolin-2(1H)-onj-4-yl or on [3,4-dihydrochinolin-2(1H)-on]-4-yl; - 1-[9H]-carbazol-4-yl;; - {spirokyclohexan-1,2'-indan]-1'-on}-4'-yl; B and p are as defined above; and R, is alkyl of 1 to 5 carbon atoms which is independently di-substituted by: phenyl; phenyl mono- or independently di-substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen of atomic number of from 9 to 35, hydroxy, cyano, trifluoromethyl, nitro, amino, alkanoylamino of 2 to 5 carbon atoms or trifluoromethyl; pyridinyl; thienyl; furyl; pyrrolyl; imidazolyl; imidazolyl monosubstituted in the 1-position by methyl; or cycloalkyl of 3 to 7 carbon atoms; with the proviso that when a) Ar, is a group of formula A as defined in part a) of the proviso under formula I above and additionally b) p and B are as defined in part b) of the proviso under formula I above, then Ra is other than diphenylalkyl of 13 to 17 carbon atoms or diphenylalkyl of 13 to 17 carbon atoms mono- or independently disubstituted in any of the phenyl rings by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35; and their corresponding physiologically hydrolyzable derivatives.

In formula la Ar, preferably is an optionally substituted indolyl or oxindolyl group as defined above, preferably an optionally substituted 4-indolyl or 4-oxindolyl group, especially an optionally substituted 4indolyl group. Another preferred group Ar, is optionally substituted phenyl, preferably substituted by hydroxy. R, preferably is alkyl disubstituted by: phenyl or substituted phenyl; or by phenyl or substituted phenyl and pyridinyl; or by pyridinyl; or by pyridinyl and thienyl; particularly, disubstituted by pyridinyl or by pyridinyl and thienyl. A substituted phenyl moiety in R. preferably is substituted by fluorine.

In a subgroup of compounds of formula la and their corresponding physiologically hydrolyzable derivatives Ar, is 4-indolyl optionally substituted as defined above.

An especially preferred group of compounds of the invention is the compounds of formula laa

wherein either R, is: hydrogen, methyl, hydroxymethyl, carboxyl, alkoxy-carbonyl of altogether 2 to 5 carbon atoms, carbamoyl or cyano and R2 is: hydrogen or methyl or R, is: hydroxy and R2 is: hydrogen; and B, p and Ra are as defined above; with the proviso that when B and p are as defined under part b) of the proviso under formula I above, then R, is other than diphenylalkyl of 13 to 17 carbon atoms diphenylalkyl of 13 to 17 carbon atoms mono- or independently disubstituted in any of the phenyl rings by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35; and their corresponding physiologically hydrolyzable derivatives.

In a subgroup of compounds of formula la and laa and their corresponding physiologically hydrolyzable derivatives R, is other than hydroxy. In another subgroup R, is cyano. In another subgroup p is 0. In another subgroup B has significance iv) above. In another subgroup B has significance iv) above wherein m is 2. in another subgroup B has a significance other than significance i) above. In another subgroup p -is 1. In another subgroup Ra is as defined above with the proviso that it is other than alkyl of 1 to 5 carbon atoms disubstituted by two phenyl groups optionally substituted as defined above.In another subgroup R, is alkyl of 1 to 5 carbon atoms disubstituted by a phenyl group optionally substituted as defined above and by another group selected from: pyridinyl; thienyl; furyl; pyrrolyl; imidazolyl; imidazolylmonosubstituted in the 1-position by methyl; and cyclo-alkyl of 3 to 7 carbon atoms. In another subgroup R, is alkyl of 1 to 5 carbon atoms which is independently disubstituted by: pyridinyl, thienyl, furyl, pyrrolyl, imidazolyl, imidazolylmonosubstituted in the 1-position by methyl, or cycloalkyl of 3 to 7 carbon atoms.In another subgroup R, is alkyl of 1 to 5 carbon atoms which is independently disubstituted by: phenyl mono- or independently disubstituted by hydroxy, cyano, nitro, amino,alkanoylamino of 2 to 5 carbon atoms or trifluoromethyl; pyridinyl, thienyl, furyl, pyrrolyl, imidazolyl or imidazolylmonosubstituted in the 1-position by methyl; or cycloalkyl of 3 to 7 carbon atoms. In another subgroup R, is alkyl of 1 to 5 carbon atoms which is independently disubstituted by phenyl mono-or independently disubstituted by hydroxy, cyano, nitro, amino, alkanoylamino of 2 to 5 carbon atoms or trifluoro-methyl. In further subgroups the symbols have the meanings indi-cated above in combination, individually or collectively.

Another group of compounds of the invention is the compounds of formula Ip

wherein Rip is: hydrogen, methyl, hydroxymethyl, carboxyl, alkoxycarbonyl of altogether 2 to 5 carbon atoms, carbamoyl or cyano; R2p is: hydrogen or methyl; either pp is 1 and Bp is: - a group ip) of formula

wherein RI is as defined above; or - a group ii) or iii) as defined above; or pp is O or 1 and Bp is: a group iv, of formula

and Rp is: alkyl independently disubstituted by aromatic, hetero-aromatic and/or cycloalkyl groups, with the proviso that Rp is other than diphenylalkyl of 13 to 17 carbon atoms or diphenylalkyl of 13 to 17 carbon atoms mono- or independently disubstituted in any of the phenyl rings by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35; and their corresponding physiologically hydrolyzable derivatives.

Another group of compounds of the invention is the compounds of formula Ip'

wherein R,p, R2p and Rp are as defined above; and their corresponding physiologically hydrolyzable derivatives.

Unless otherwise specified elsewhere preferred significances are: - for alkyl: methyl or ethyl, especially methyl; - for alkoxy: methoxy or ethoxy, especially methoxy; - for halogen: chlorine or bromine, especially chlorine; - for cycloalkyl: cyclopentyl or cyclohexyl, especially cyclohexyl; - for alkoxycarbonyl: methoxy- or ethoxycarbonyl, especially methoxy carbonyl; when it is of more than 2 carbon atoms it preferably is branched in the position a to the carbonyl moiety, as in isopropoxycarbonyl; - for alkoxyalkyl: methoxymethyl or (2-methoxy)ethyl; - for alkoxycarbonylalkyl: ethoxycarbonylmethyl.

In accordance with the invention, a compound of the invention may be obtained by a process which includes the step of appropriately 3-amino-2-oxypropylating a corresponding compound of formula IV,

wherein Ar is as defined above, or a precursor form thereof.

The process step of the invention may be effected in conventional manner for the production of analogous 3-amino-2-oxy-propoxyaryl compounds.

The choice of the most appropriate variant should, of course, take into account the reactivities of the substituents present.

Preferably a compound of formula IV is used, rather than a precursor form thereof.

A precursor form of a compound of formula IV is a compound capable of being converted into a compound of formula IV, e.g. by appropriate acylation or deprotection. Thus, for alkoxy-carbonyl, a precursor group is e.g. carboxyl, and vice-versa. For hydroxy, a precursor group is e.g. benzyloxy. For a ring system a precursor group may e.g. be the corresponding uncyclized group. For a substituted amino moiety a precursor group may e.g. be the corresponding unsubstituted amino moiety. For amino a precursor group may e.g. be nitro.

Thus, the process step of the invention may be effected in more than one stage. For example, a compound of formula IV in protected form may be used, or a 3-amino-2-oxypropyl moiety in protected form may be introduced, and subsequently, after the 3-amino-2-oxypropylation has been effected, a complementary reaction step may be effected, e.g. any protecting group present may be split off.

Benzyl, methyl or tetrahydropyranyl, preferably benzyl, are examples of a protecting group.

In one form of the process according to the invention, the 3-amino-2-oxypropylation is effected in two main stages.

In a first stage, a group -CH2-R,, wherein R, is a group capable of reacting with a primary or secondary amine to give a 2-amino-1-hydroxyethyl group, is introduced by O-alkylation into a compound of formula IV to give a corresponding compound of formula II

wherein Rx and Ar are as defined above.

In a second stage, a compound of formula II is reacted with a corresponding compound of formula III, H-(CO)p-R III wherein p and R are as defined above, and where required the 2-position of the 3-aminopropoxy side chain in a resultant compound of formula I is appropriately esterified.

The O-alkylation stage may be effected in a manner known for the production of analogous ethers. A compound of formula IV preferably is reacted in anionic form.

The amination stage may be effected in conventional manner for the production of analogous 3-amino2-hydroxypropoxyaryl compounds. For example, R, may be a group of formula

or a derivative of this group, e.g. a group of formula -CH(OH)-CH2L, wherein L is chlorine, bromine or a group RV-SO2-O- wherein Ry is phenyl, tolyl or lower alkyl. L is especially chlorine. The reaction is preferably effected in ethanol or in an appropriate ether such as dioxane. Optionally an excess of the amine may be used as solvent. Alternatively the reaction may be effected in a fusion melt. Suitable reaction temperatures may be from about 20 to about 200"C, conveniently the reflux temperature of the reaction mixture when a solvent is present.

The optional esterification of the hydroxy group in the propoxy side chain may be effected in manner known for the production of analogous esters of 3-amino-2-hydroxypropoxyaryl compounds, if necessary using selective reactions when other reactive groups, e.g. amino, are present.

The compounds of the invention may exist in free form, i.e. normally as a base, or in salt form, e.g.

acid addition salt form. Free forms of the compounds of the invention may be converted into salt forms and vice versa, in conventional manner. Suitable acids for acid addition salt formation include hydrochloric, malonic and fumaric acid.

In the compounds of the invention the carbon atom in e.g. the 2 position of the propoxy side chain is asymmetrically substituted. The compounds may thus exist in the racemic form or in individual optical isomer form. The preferred optical isomer has the S-configuration at this asymmetrically substituted carbon atom of the propoxy side chain. Individual optical isomer forms may be obtained in conventional manner, for example by using optically active starting materials or by fractional crystallisation of diaster eoisomeric salts formed with optically active acids.

When R is e.g. alkyl disubstituted by two different groups a further asymmetry center is present. These compounds may thus exist as a mixture or as two separate racemates or in pure enantiomer form. Individual diastereoisomer forms may also be obtained in conventional manner as described above, e.g. by: 1) chromatography using optically active adsorbants, e.g. acylated cellulose derivatives or polymeric aminoacid derivatives; 2) fractional crystallization of salts using optically active acids for salt formation; or 3) using a corresponding optically active starting material; in this situation separation may be effected at an intermediate stage.

Insofar as the preparation of any particular starting material is not particularly described this is known or the preparation may be effected in conventional manner or as described in the Examples or in a manner similar thereto.

In the following Examples all temperatures are in degrees Centigrade and are uncorrected.

Example 1: fS)-4-[3-[4-63,3tdithienylmethyl)piperazin- 1-yI]-2-h ydroxyprop oxy]- 1H-indol-2-carbonitrile 1.5 g (S)-4-(2,3-epoxypropoxy)-1H-indol-2-carbonitrile and 1.85 g 1-(3,3'-dithienylmethyl)piperazine are melted together at 70 . The product is chromatographed over silicagel. The title compound is obtained (foam; [OL]2DO -15.4", c= 1% in chloroform).

The epoxide used as a starting material is obtained as follows: a) 80 g (S)-2,2-dimethyl-1,3-dioxolan-4-methanol dissolved in dimethylformamide are reacted at 0" with potassium hydroxide and thereafter with benzyl bromide. (S)-4-Benzyloxymethyl-2,2-dimethyl-1,3-dioxolan is obtained (clear oil; [ae]D =+9.6 , c= 2 % in methanol).

b) 93.3 g of the above product in hydrochloric acid aqueous solution and acetone are reacted under refluxing for 2 hours. (R)-3-Benzyloxypropan-1,2-diol is obtained (colourless oil; [0112,0 = -1.2", c= 2% in methanol).

c) 118 g of the above product in pyridine are reacted at 0" dropwise with 126.5 g of p-toluene sulfonic acid chloride in benzene and the mixture is stirred for 72 hours at room temperature. (S)-1-Benzyloxy-3tosyloxy-2-propanol is obtained (oil; [a]2D0 = +8.3 , c= 2% in methanol).

d) 41 5 g of 4-Hydroxy-1H-indol-2-carboxamide are converted with sodium hydride into the corresponding sodium salt and this salt is reacted in dimethyl formamide with 87.8 g of the product obtained under c). The mixture is stirred for 40 hours at 100" oil bath temperature. After working up and chromatographic purification over silicagel (S)-4-(3-Benzyloxy-2-hydroxypropoxy)-1 H-indol-2-carboxamide is obtained (M.P. 115-117"; [oL]2,D = -1.5', c = 2% in methanol).

e) 62.2 g of the above product are hydrogenated for 6 hours with palladium 10 % on charcoal in methanol. (S)-4-(2,3-Dihydroxypropoxy)-1H-indol-2-carboxamide is obtained (M.P. 183-185"; [a]2,0 = +6.15 , c= 2% in methanol).

f) 36.65 g of the above product are dissolved in pyridine and reacted for 1 hour at -15" to -5" with a solution of p-toluenesulfonic acid chloride in pyridine and the mixture stirred for 3 hours at 0 .

(R)-4-(2-Hydroxy-3-tosyl oxypropoxy)-l H-indol-2-ca rboxam ide is obtained (MP. 162-168 [ol]B = - 13.50, c= 2% in methanol).

g) A solution of 44.2 g of the above product in methanol/tetrahydrofurane (1:1) is added dropwise at 0 to a solution of 2.76 g sodium in methanol over 1 1/2 hours and stirred for one hour. (S)-4-(2,3-Epoxypropoxy)-1H-indol-2-carboxamide is obtained (M.P. 125-135"; [oL]i' = +260, c= 2 % in methanol).

h) 7.9 g of the above product are suspended in dioxane and pyridine and a solution of 7.8 ml trifluoroacetic acid anhydride in dioxan is added thereto at 10 over 1 hour and the mixture is stirred for another hour. (S)-4-(2,3-Epoxypropoxy)-1H-indol-2-carbonitrile is obtained (M.P. 123-125"; [ol]B = +40.00, c = 1 % in methanol).

The amine used as a starting material is obtained as follows: a) 8.2 g of 3,3'-dithienylcarbinol in methylene chloride and 8.45 g triethylamine are cooled to -70 and a solution of 4.79 g methanesulfonic acid chloride in methylene chloride is added dropwise. After 1 hour a solution of 6.62 g N-ethoxycarbonylpiperazine in methylene chloride is added, the mixture is stirred for 1 hour and the temperature allowed to increase to room temperature. After chromatography over silicagel 4-(3,3'-dithienylmethyl)-1-piperazinecarboxylic acid ethyl ester is obtained (oil).

b) 10.35 g of the above ester are heated for 2 hours with 60 ml methanol, 60 ml dimethyl sulfoxide and 120 ml of a 30% aqueous sodium hydroxide solution. 1-(3,3'-Dithienylmethyl)piperazine is obtained (M.P.

102-104").

The following compounds of formula I are obtained in a manner analogous to Example 1 (unless specified otherwise in the footnotes) starting from corresponding compounds of formula II wherein R, is

by reaction with corresponding compounds of formula III:

Config. Where of OH- appropri carrying ate: con C* of fig. of C* Ex. Ar B P R propoxy of group R M.P. [α]D20 No. chain 1. Ar = an indole group 1.1. B = piperazine 210) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O di(2-thienyl)methyl rac. n.a. b foam n.a. 3) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O di(4-NO2-phenyl) rac. n.a. dch 205-208 n.a. methyl 4 ) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (cyclohexyl)- S rac. b foam -17.3 CHCH2- (c=1% in CHCl3) 4a a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (cyclohexyl)- S A b foam CHCH24b a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe) (cyclohexyl)- S B b foam CHCH25) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O di(4-CN-phenyl)- S n.a. fu 170-172 -2.8 methyl (c=2% in CH3OH) 64) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O di(4-NH2-phenyl)- S n.a. b foam methyl 75) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O di(r-MECONH-phenyl)- S n.a. b foam methyl

Config. Where of OH- appropri carrying ate: con C* of fig. of C* Ex. Ar B P R propoxy of group R M.P. [α]D20 No. chain 86) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O di(4-pyridinyl) S n.a. b foam methyl 97) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (4-OH-Phe)(phenyl)- rac. n.a. b foam methyl 9a a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (4-OH-Phe)(phenyl)- S A b foam methyl 9b a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (4-DH-Phe)(phenyl)- S B b foam methyl 108) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (dicyclohexyl)- S n.a. b foam methyl 119) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O di(4-CF3-phenyl)- S n.a. b foam -8.8 methyl (c=1% in CH3OH) 11a14) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(pyridin- S rac. b foam 4-yl)methyl 123a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(pyridin- S A b foam +6.8 4-ylmethyl (c=1% in ethanol) 13 a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(pyridin - S B b foam +8.0 4-yl)methyl (c=1% in ethanol) 146) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O di(2-pyridinyl)- S n.a. b foam +7.3 methyl (c=1% in CH3OH)

Config. Where of OH- appropri carrying ate: con C* of fig. of C* Ex. Ar B P R propoxy of group R M.P. [α]D20 No. chain 14a14) 2-CN-1H-indol-4-yl Piperazin-1,4-diyl O (Phe)(pyridin-3- S rac. b foam yl)methyl 15 a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(pyridin-3- S A b foam +4.5 yl)methyl (c=1% in ethanol) 16 a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(pyridin-3- S B b foam +3.6 yl)methyl (c=1% in ethanol) 1715) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (3-thienyl)(4- S rac. b foam pyridinyl)methyl 17a a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (3-thienyl)(4- S A b foam pyridinyl)methyl 17b a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (3-thienyl)(4- S B b foam pyridinyl)methyl

Config. Where of OH- appropri carrying ate: con C* of fig. of C* Ex. Ar B P R propoxy of group R M.P. [α]D20 No. chain 188) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O dicyclohexyl- S n.a. b foam -8.5 methyl (c=1% in CH3OH) 1916) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(2-thie- S rac. b foam +5.2 nyl)methyl (c=1% in CH3OH) 19a a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(2-thie- S A b foam nyl)methyl 19b a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(2-thie- S B b foam nyl)methyl 2016) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(3-thie- S rac. b foam +5.5 nyl)methyl (c=1% in CH3OH) 20a a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(3-thie- S A b foam nyl)methyl 20b a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(3-thie- S B b foam nyl)methyl 20c) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (3-pyridinyl)- S rac. b foam (3-thienyl) methyl 21 a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (3-pyridinyl) - S A b foam +6.8 (3-thienyl)- (c=1% in methyl CH3OH) 22 a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (3-pyridinyl)- S B b foam +4.9 (3-thienyl)- (C=1% in methyl CH3OH)

Config. Where of OH- appropri carrying ate: con C* of fig. of C* Ex. Ar B P R propoxy of group R M.P. [α]D20 No. chain 236) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O di(3-pyridinyl)- S n.a. b foam +6.2 methyl (c=1% in CH3OH) 23a ) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(1-Me-2- S rac. b foam imidazolyl)methyl 24 a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(1-Me-2- S A b foam +7.0 imidazolyl)methyl (c=1% in CH3OH) 25 a) 2-CN-1H-indol-4-yl piperazin-1,4-diyl O (Phe)(1-Me-2- S B b foam +5.2 imidazolyl)methyl (c=1% in CH3OH) 25a 2-CN-1H-indol-5-yl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b foam n.a. 25b 2-CN-1H-indol-6-yl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 167-168 n.a.

Config. Where of OH- appropri carrying ate: con C* of fig. of C* Ex. Ar B P R propoxy of group M.P. [α]D20 No. chain R 26 2-acetyl-1H-indol- Piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 186-188 n.a. 4-yl 2718) 3-CN-1H-indol-4-yl Piperazin-1,4-diyl O diphenylmethyl rac. n.a. fu 230-231 n.a. 2819) 6-COOH-1H-dinol-4- Piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 145-148 n.a. yl 2920) 6-COOMe-1H-indol- Piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 110-111 n.a. 4-yl 30) 7-CH2CH2OEt-1H- Piperazin-1,4-diyl O diphenylmethyl rac. n.a. mo 107-110 n.a. indol-4-yl 31) 7-CH2CH2OMe-1H- Piperazin-1,4-diyl O diphenylmethyl rac. n.a. hml 105-107 n.a. indol-4-yl 32 ) 2,3-diCN-1H-indol- Piperazin-1,4-diyl O diphenylmethyl rac. n.a. b foam n.a. 4-yl 3324) 2-CN-1-Me-1H-indol- Piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 150-152 n.a. 4-yl 3425) 2-CN-1-CH2COOEt- Piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 142-144 n.a. indol-4-yl 3525) 2-CN-1-COOEt- Piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 149-151 n.a. indol-4-yl

Config. Where of OH- appropri carrying ate: con C* of fig. of C* Ex. Ar B P R propoxy of group M.P. [α]D20 No. chain R 35a ) 2-CN-3-CH2NMe2- Piperazin-1,4-diyl O diphenylmethyl rac. n.a. tch 203 n.a. 1H-indol-4-yl 35b) 2-CN-3-Me-1H- Piperazin-1,4-diyl O (Phe)(pyridin- rac. rac. b 169-170 indol-4-yl 4-yl) methyl 35c a) 2-CN-3-Me-1H- Piperazin-1,4-diyl O (Phe)(pyridin- S A b foam indol-4-yl 4-yl)methyl 35d a) 2-CN-3-Me-1H- Piperazin-1,4-diyl O (Phe)(pyridin- S B b foam indol-4-yl 4-yl)methyl 35e41) 7-F-1H-indol- Piperazin-1,4-diyl O diphenylmethyl rac. n.a. bml 154-156 n.a. 4-yl

Config. Where of OH- appropri carrying ate: con C* of fig. of C* Ex. Ar B P R propoxy of group M.P. [α]D20 No. chain R 1.2. B= piperidine # O diphenylmethyl S n.a. b foam -19.4 (c=1% in CHCl3) 37 2-CN-1H-indol-4-yl # O di(4-F-phenyl) rac. n.a. b 179-181 n.a. methyl 1.3. B = another gruop # O diphenylmethyl rac. n.a. b foam n.a. 3927) 2-CN-1H-indol-4-yl # O diphenylmethyl rac. n.a. b 156-159 n.a. 4028) 2-CN-1H-indol-4-yl # -N(Me)- O diphenylmethyl rac. n.a. b 125-128 n.a. 4129) 2-CN-1H-indol-4-yl # -NH- O diphenylmethyl rac. n.a. zml 192-194 n.a. 42 2-CN-1H-indol-4-yl -N(Me)-#- O diphenylmethyl S n.a. b foam -33.2 (c=1% in CHCl3) 42a 2-CN-1H-indol-4-yl -NH-#- O diphenylmethyl S n.a. b foam -8.5 (c=1% in CHCl3)

Config. Where of OH- appropri carrying ate: con C* of fig. of C* Ex. Ar B P R propoxy of group M.P. [α]D20 No. chain R 2. Ar = an oxindole group 4328 2,30dihydro-2-oxo- #-N(Me) O diphenylmethyl S n.a. b 170-172 n.a. 1H-indol-4-yl 4429) 2,3-dihydro-2-oxo- #-NH- O diphenylmethyl rac. n.a. b 154-156 n.a. 1H-indol-4-yl 4527) 2,3-dihydro-2-oxo- -N(Me)CH2CH2N(Me)- O diphenylmethyl rac. n.a. b 140-142 n.a. 1H-indol-4-yl 45a 2,3-dihydro-2-oxo- NH-#- O diphenylmethyl rac. n.a. b 106-108 n.a. 1H-indol-4-yl 46 2,3-dihydro-3,3- piparazin-1,4-diyl O diphenylmethyl rac. n.a. zml 108-112 n.a. dime-2-oxo-1H indol-4-yl 46a14) 2,3-dihydro-2-oxo- piperazin-1,4-diyl O (Phe)(pyridin- rac. n.a. b 154-155 1H-indol-4-yl 4-yl)methyl 46b a) 2,3-dihydro-2-oxo- piperazin-1,4-diyl O (Phe)(pyridin- rac. rac. b 1H-indol-4-yl 4-yl)methyl 46c a) 2,3-dihydro-2-oxo- piperazin-1,4-diyl O (Phe)(pyridin- S A b foam 1H-indol-4-yl 4-yl)methyl

Config. Where of OH- appro carrying priate: C* of config.of Ex. Ar B P R propoxy C* of M.P. [α]D20 No. chain group R 3. Ar = another polycyclic aryl group 47 ) 2,1,3-benzoxa- Piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 125-126 n.a. diazol-4-yl 4834) 2-CF3-benzimid- piperazin-1,4-diyl O diphenylmethyl rac. n.a. fr 222 n.a. azol4-yl 4934) benzimidazol- piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 176-178 n.a. 4-yl 5034) 1,2-dihydro-2-oxo- piperazin-1,4-diyl O diphenylmethyl rac. n.a. ch 265-267 n.a. benzimidazol-4-yl

Config. Where of OH- appropri carrying ate: con C* of fig. of C* Ex. Ar B P R propoxy of group M.P. [α]D20 No. chain R 51 [chino]in-2(1H)- piperazin-1,4-diyl O diphenylmethyl rac. n.a. fu 214-217 n.a. on]4-yl 52 [3,4-dihydro- piperazin-1,4-diyl O diphenylmethyl rac. n.a. fu 218-219 n.a. chino]in-2(1H) on]-4-yl 53 [3,4-dihydro- piperazin-1,4-diyl O di(4-F-phenyl) rac. n.a. - n.a. chino]in-2(1H)- methyl oxo]-4-yl 54 1-[9H]-carbazol- piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 200-202 n.a. 4-yl 55 # piperazin-1,4-diyl O diphenylmethyl rac. n.a. hfu 169-170 n.a. 56 # -NH-# O diphenylmethyl rac. n.a. zml 165-168 n.a. 57 # -#-NH- 1 diphenylmethyl rac. rac. b 201-202 n.a.

Config. Where of OH- appropri carrying ate: con C* of fig. of C* Ex. Ar B P R propoxy of group M.P. [α]D20 No. chain R 4. Ar = a phenyl group 57a 4-OBz-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 106-108 n.a. 5836) 4-OH-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. fu 155-159 n.a. 58a) 3-OBz-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b oil n.a. 5836) 3-OH-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 183-185 n.a. 59a 3-COOMe-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b oil n.a. 6035) 3-COOH-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 190-191 n.a. 61 3-CF3-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. fu 180-182 n.a. 6237) 4-MeCOCH2-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 108-110 n.a. 62a38) 3-NH2-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b oil n.a. 6339) 3-NHSO2Me-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b foam n.a. 6440) 3-NHCH2CH-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. bfu 131-133 n.a. 65 3-NHCOMe3-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. mo 117-119 n.a. 66) 2-(1-hydroxyme- piperazin-1,4-diyl O diphenylmethyl rac. n.a. fu 154-155 n.a. thylcyclohexyl) methylphenyl 67 2-(1-acetoxyme- piperazin-1,4-diyl O diphenylmethyl rac. n.a. fu 162-164 n.a. thylcyclohexyl) methylphenyl

Config. Where of OH- appropri carrying ate: con C* of fig. of C* Ex. Ar B P R propoxy of group M.P. [α]D20 No. chain R 67a17) # piperazin-1,4-diyl O diphenylmethyl rac. n.a. b foam n.a. 68) # piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 177-180 n.a., 68a 3,5-di-OBz-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b foam n.a. 6926) 3,5-di-OH-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 193-184 n.a. 69a 2-CN-4-OBz-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b oil n.a. 7030) 2-CN-4-OH-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. fu 196-198 n.a.

Config. Where of OH- appropri carrying ate: con C* of fig. of C* Ex. Ar B P R propoxy of group M.P. [α]D20 No. chain R 71 2-acetyl-4- piperazin-1,4-diyl O diphenylmethyl rac. n.a. fu 161-163 n.a. OCH2CH2OMe-phenyl 72 2-CN-4-OCH2CH2OMe- piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 107-109 n.a., phenyl 73 2-Me-3-NO2-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b 149-150 n.a. 74 2,3-di-NO2-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. b foam n.a. 75 ) 2,3-di-NH2-phenyl piperazin-1,4-diyl O diphenylmethyl rac. n.a. dch 133- n.a. 135

Glossary: C W = asymmetric carbon atom config. = configuration rac. = racemic n.a. = not applicable Bz = benzyl Me = methyl Phe = phenyl Et = ethyl bml = in bis[maleate]salt form dch = in dihydrochloride salt form b = in free form fu = in fumarate salt form mo = in malonate salt form zml = in bis[hydrogen maleate]salt form hml = in hydrogen maleate salt form ch = in hydrochloride salt form hfu = in hydrogen fumarate salt form bfu = in bisfumarate salt form tch = in trihydrochloride salt form A = in one of the two possible stereoisomeric forms B = in the other of the two possible stereoisomeric form dec. = decomposition Reaction conditions and preparation of intermediates:: 1'1-[Bis(4-nitrophenyl)methyl]piperazine is obtained by acetylation of 1-diphenylmethyl-piperazine followed by nitration of the resultant acetylpiperazine followed by splitting off of the acetyl group from the resultant dinitro derivative.

2)1 -[Bis(4-cyanophenyl)methyl]piperazine is obtained by reduction of di-(p-cyanophenyl)ketone with NaBH, followed by mesylation of the resultant alcohol followed by reaction of the resultant mesylate with N-formylpiperazine followed by hydrolysis of the resultant N-formylpiperazine derivative.

3'1-[(2-Cyclohexyl-2-phenyl)ethyl]piperazine is obtained by acylation of 1-benzylpiperazine with 2phenyl-2-cyclohexylacetic acid chloride followed by reduction of the resultant derivative with LiAIH4 followed by N-debenzylation of the resultant derivative by hydrogenation with palladium on charcoal.

3a'The corresponding mixture of diastereoisomeres of formula I is fractionated into its two optically pure components by chromatography on silicagel.

4'1-[Bis(4-aminophenyl)methyllpiperazine is obtained by reduction of the nitro derivative described under 1).

5X1-[Bis-(4-acetaminophenyl)methyl]piperazine is obtained by acetylation of the amino derivative described under 4).

eThe corresponding 1-[bis(pyridinyl)methyl]piperazine is obtained by reduction of the corresponding (dipyridinyl)ketone with NaBH4 followed by mesylation of the resultant alcohol followed by reaction of the resultant mesylate with N-formylpiperazine followed by splitting off of the formyl group from the resultant N-formylpiperazine derivative.

711-[(4-Hydrnxyphenyl)-phenylmethyl]pipernzine is obtained by reduction of phenyl-(p-benzyl-oxypheny)ketone with NaBH4 followed by bromosubstitution with PBr2 of the free hydroxy group in the resultant alcohol followed by reaction of the resultant bromo derivative with benzylpiperazine followed by splitting off of the benzyl and benzyloxy groups from the resultant N-benzylpiperazine derivative by hydrogenation with palladium on charcoal.

3'1-[Bis(cyclohexyl)methyl]piperazine is obtained by mesylation of dicyclohexylcarbinol followed by reaction of the resultant mesylate with formylpiperazine followed by splitting off of the formyl group from the resultant N-formylpiperazine derivative.

91-[Bis(4-trif luoromethylphenyl )methyl]piperazine is obtained by bromosubstitution with PBr, of the free hydroxy group in di-(p-trifluoromethylphenyl)carbinol followed by reaction of the resultant bromo derivative with formylpiperazine followed by splitting off of the formyl group from the resultant N-formylpiperazine derivative.

l0IThe corresponding l-[bis(thienyl)methyI]piperazine is obtained as described in Example 1, starting from the corresponding di-(thienyl)ketone.

)The title compound is obtained for alkaline hydrolysis of the Example 67 compound.

12)1-[(3-Pyridinyl)-3'-thienyl)methyl]piperazine is obtained in a manner analogous to that described underfootnote 15).

13)1-[(1-Methyl-2-imidazolyl)(phenyl)methyl]piperazine is obtained in a manner analogous to that described under footnote 16). The carbinol is prepared by reaction of 2-lithio-1-methyli-midazol with benzaldehyde.

14)The corresponding 1-[(Pyridinyl)(phenyl)methyl]piperazine is obtained by reaction of the corresponding carbinol with ethoxycarbonylpiperazine at elevated temperature followed by hydrolysis of the resultant carbethoxy compound.

ISX1-[(4-Pyridinyl)(3'-thienyl)methyl]piperazine is obtained in 2 steps from the corresponding carbinol as described under footnote 8). The carbinol is prepared by reaction of 3-thienyl-lithium with pyridine-4-carboxaldehyde.

Is)The corresponding 1-[(phenyl)(thienyl)methyljpiperazine is obtained by reaction of the corresponding carbinol with thionyl chloride followed by condensation of the resultant chloride with ethoxycarbonylpiperazine followed by hydrolysis of the resultant carbethoxy compound.

ilIThe title compound is obtained by reaction of the Example 62 compound with N,N-dimethylformamide dimethylacetal.

18)4-92,3-Epoxypropoxy)-1H-indol-3-carbonitril (M.P. 125-126 ) is obtained by reaction of 4-(2,3-epoxypropoxy)-1H-indol with chlorosulfonylisocyanate followed by reaction of the resultant 3-cyano compound with benzhydrylpiperazine.

9lBy hydrolysis of the compound of Example 29 with aqueous sodium hydroxide solution.

20)4-Hydroxy-6-methyoxycarbonyl-1H-indol (M.P. 80-81") is obtained by the following reaction sequence: Stobbe condensation of pyrrol-2-aldehyde with dimethyl succinate followed by cyclization of the resultant compound with acetic anhydride/ sodium acetate to 4-acetoxy-6-methoxycarbonylindole followed by treatment with sodium methoxide in methanol.

21sThe title compound is obtained by reacting the Example 67a compound with cyanacetamide in sodium ethylate.

22)4-Hydroxy-7-(2-methoxyethyl)-1H-indol (oil) and 4-hydroxy-7-(2-ethoxyethyl)-1H-indol (oil) are obtained by formylation of 4-benzyloxy-1 H-indol-2-carboxylic acid ethyl ester followed by hydrolysis of the resultant 4-benzyloxy-7-formyl-1H-indol-2-carboxylic acid ethyl ester (M.P. 113-114") followed by decarboxylation of the resultant 4-benzyloxy-7-formyl-1H-indol-2-carboxylic acid (M.P. 203-206") followed by NABH4-reduction of the resultant 4-benzyloxy-7-formyl-1 H-indole (M.P. 129-131") followed by acetylation of the resultant 4-benzy-loxy-7-hydroxymethyl-l H-indole (M.P. 82-84") followed by reaction of the resultant 4-benzyloxy-7-acetyloxymethyl-1H-indole (M.P. 70-71") with NaCN followed by hydrolysis of the resultant 4-benzyloxy-1 H-indol-7-acetonitrile (M.P. 152-1 54Q) followed by reduction of the resultant 4benzyloxy-1H-indol-7-acetic acid (M.P. 133-136") followed by corresponding etherification of the resultant 4-benzyloxy-7-(2-hydroxyethyl)-1 H-indole (M.P. 62-64") with diazomethane or, respectively, diazoethane followed by debenzylation of the resultant ether.

2314-(2,3-Epoxypropoxy)-l H-indol-2,3-dicarbonitrile (M.P. 172-174") is prepared by reaction of 4-(2,3epoxypropoxy)-l H-indol-2-carbonitrile with chlorosulfonylisocyanate in dimethylformamide.

24'The title compound is obtained by methylation with dimethyl sulfate of 4-[3-(4-diphenylmethylpipera zin-1-yl)-2-hydroxy-propoxy]-1H-indol-2-carbonitrile with tetrabutylammonium iodide in a solution of methylene chloride and aqueous sodium hydroxide for 30 minutes and chromatography of the resultant compound over silicagel using methylene chloride/5% methanol as an eluent.

25)The title compound is obtained by reaction of 4-[3-(4-diphenylmethylpiperazin-1 -yl)-2-hydroxypropoxy)-1H-indol-2-carbonitrile with chloracetic acid ethyl ester (Example 34) or, respectively, chloroformic acid ethyl ester (Example 35).

26'The title compound is obtained by debenzylation of the Example 68a compound.

27)N-(Diphenylmethyl)-N,N'-dimethylethylenediamine (oil) is obtained by reaction of MeCON(Me)CH,CH2Cl with N-diphenylmethyl-N-methylamine in dioxane and hydrolysis of the resultant acetamide with sodium hydroxide/ethanol.

28)4-(N-Diphenylmethyl-N-methylamino)piperidin (M,P 116-120 ) is obtained by hydrogenation of 1-carbethoxy-4-piperidone over platinum oxide followed by N-methylation of the resultant amine (M.P. 78-80") with formaldehyde in formic acid followed by hydrolysis of the resultant compound (M.P. 146-148") with potassium hydroxide/ethanol.

29)4-(Diphenylmethylamino)piperidin (M.P. 67-69 ) is obtained by hydrolsis of the intedrmediate amine of M.P. 78-80 described in footnote 28), with potassium hydroxide/ ethanol.

30)The title compound is obtained by debenzylation of the Example 69a compound.

3a'The title compound is obtained by reaction of 4-[3-(4-diphenylmethylpiperazin-1-yl)-2-hydroxypro- poxy]-1 H-indol-2-carbonitrile with formaldehyde and dimethylamine.

32)4-Hydroxy-2,1,3-benzoxadiazol is obtained by reaction of 2, 6-dichloraniline with hydrogen peroxide followed by reaction of the resultant 2,6-dichloronitrosobenzene (M.P. 162-163") with sodium azide followed by reaction of the resultant 4-chloro-2,1,3-benzoxadiazol (M.P. 75-79") with sodium methylate fol lowed by acid hydrolysis of the resultant 4-methoxy-2,1 ,3-benzoxadiazol (M.P. 76-78").

33'The title compound is obtained by hydrogenation of the Example 74 compound with palladium on charcoal.

34'The title compound is obtained by cyclization of the Example 75 compound with, respectively, trifluoroacetic acid anhydride (Example 48), HC(OEt)3 (Example 49) or COCI2 (Example 50).

35,The title compound is obtained by alkaline hydrolysis of the Example 59a compound.

36The title compound is obtained by debenzylation of the corresponding compound having a benzyl group in place of hydroxy (Example 57a, 58a compounds) 37r[(4-Hydroxy) benzyl]methyl ketone is obtained by demethylation of [(4-methoxy)benzyl]methyl ketone with hydrobromic acid.

39'The title compound is obtained by alkaline hydrolysis of the Example 65 compound.

39rThe title compound is obtained by reaction of the Example 62a compound with CH3SO2CI.

40,3-Cyanomethylaminophenol (oil) is obtained by reaction of 3-aminophenol with chloroacetonitrile.

4"The starting material is obtained according to the following reaction sequence: 4-Fluorophenol B 2-bromoderivative < 2-bromo benzyloxy derivative

2-cyano benzyloxy derivative z 2-formyl benzyloxy derivative

benzyloxy derivative

4-benzyloxy-74luoro-1 H-indol-2-carbo,xylic acid ethyl ester

corresponding acid

7-fluoro-4-benzyloxy-1 H-indole debenzylation) 7-fluoro-4-hydroxy-1 H-indole corresponding epoxide The compounds of the invention possess pharmacological activity. They are indicated for use as pharmaceuticals.

The compounds possess cardiotonic activity, as indicated by standard tests. For example, in the normotonic Numal anaesthetized dog [R. Salzmann et al., J.Cardiovasc. Pharm.7 (1985)] an increase in the contractile force of the left ventricle is observed upon intravenous administration of from about 0.01 mg/ kg to about 2 mg/kg and upon intraduodenal administration of from about 0.02 mg/kg to about 2 mg/kg.

The test method is as follows: Dogs of either sex weighing from 10 to 15 kg are used. Numal in a dosis of 65 mg/kg i.v. is used as an anaesthetic. The animal is attached in supine position on the operation table. After the usual preparations have been effected, a heparinized catheter is introduced along the Arteria carotis dextra into the left ventricle -under radiologic control and the transmission of the pressure is registered with a donor membrane (Gould Statham P 23 Gb). The increase in pressure as a function of time is computed and registered with an HSE-physiodifferentiator. The pressure increase in the left ventricle is a measure of the contractile force of the heart. The magnitude of the pressure differential is indicated in mm Hg/sec. A suitable body temperature (about 36 to 37"C) is maintained constant.After a control period of about 40 minutes the test substance is injected into the Vena femoralis and its effect on the registered or computed parameters observed.

This effect may be confirmed using similar dosages in the Inactin anaesthetized rat test [method as above, using rats anaesthetized with Inactin in place of Numal dogs], in the pithed open-chest cat test [R.

Salzmann et al., J. Cardiovasc. Pharm. 7 (1985) with direct measurement of contractile force] and in the spontaneously-beating, acutely insufficient rabbit heart test [G. Scholtysik et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1985)].

The compounds are therefore indicated for use as cardiotonic agents. e.g. for the treatment of heart insufficiency. In this indication they have a more balanced profile of activity than known cardiotonic compounds of analogous structure.

Preferred in this indication are the compounds of Examples 1, 3, 12, 13, 14, 15, 17, 21, 36, 38, 43 and 59, especially of Examples 12 and 21.

As indicated daily dosage is from about 1 mg to about 500 mg suitably administered, e.g. orally, in divided doses of from about 0.25 mg to about 250 mg 2 to 4 times a day or in sustained release form.

The compounds also exhibit antiarrhythmic activity, as indicated in standard tests. For example, they prolong the functional refractory period in the left guinea pig atrium at a concentration of from 10-7 M to 104 M [R. Hof and G. Scholtysik, J.Cardiovasc. Pharm. 5 (1983) 176-183].

The compounds are therefore indicated for use as antiarrhythmic agents, e.g. for the treatment of heart rhythm disorders such as supraventricular tachycardia or fibrillation.

The compounds also exhibit a-adrenoceptor blocking activity, as indicated by standard tests. For example, the inhibition of oi-adrenoceptors may be observed in isolated spiral strips of the Vena femoralis of dogs (E. Müller-Schweinitzer and E. Stürmer, Br.J.Pharmacol [1974]51-, 441-446) at a bath concentration of from about'l0-7 M to about 10-5 M.

The compounds are therefore indicated for use as a-adrenoceptor blocking agents, e.g. for the prophylaxis and treatment of disorders related to a paralysis of intestine motility, such as paralytic ileus.

The compounds also possess ss-adrenoceptor blocking activity, as indicated by standard tests. For example, in the isolated, spontaneously-beating guinea pig atrium [A. Bertholet et al., Postgrad-Med.J.

(1981) 57 (Suppl) 9-17] inhibition of the positive inotropic effect of adrenaline is observed at a bath concentration of about 10-9 M to about 10.6 M.

The compounds are therefore indicated for use as p-adrenoceptor blocking agents, e.g. for the prophylaxis and treatment of coronary diseases such as angina pectoris, of conditions resulting from sympathetic overstimulation, such as nervous heart ailments, of hypertension, of myocardial infarct, for interval migraine treatment, and for the treatment of glaucoma and thyreotoxicosis.

For the above-mentioned antiarrhythmic and a- and ss-adrenoceptor blocking uses an indicated daily dosage is from about 0.1 mg to about 500 mg suitably administered, e.g. orally, in divided doses of from about 0.025 mg to about 250 mg 2 to 4 times a day or in sustained release form.

Further the compounds exhibit effects typical of calcium antagonists. They exhibit a pronounced muscle-relaxing effect, particularly on smooth muscle, as evidenced by vasodilating and blood pressure lowering activity in standard tests. For example in the anaesthetized cat test using tracer microspheres (R.

Hof et al., Basic Res.Cardio/. 75 [1980] 747-756 and 76 [1981] 630-638; R. Hof et al., J.Cardiovasc.Pharmacol. 4 [1982] 352-362) coronary vasodilation, and increase in skelettal muscle blood flow and a fall in blood pressure are ovserved upon intravenous administration of from about 3llg/kg to about 300 ijg/kg.

A fall in blood pressure is also observed in the conscious spontaneously hypertensive rat (method of Gerald M. Tschirki, Arzneimittelforsch. 18 [1968] 1285) upon administration of from about 1 Ag/kg to about 100 Ag/kg s.c. of the compounds.

The compounds are therefore indicated for use als calcium antagonists for the prevention and treatment of - coronary insufficiency, e.g. angina pectoris; - disturbances in cerebral circulation such as cerebrovascular insufficiency; cerebrovascular insults, e.g.

stroke; and cerebrovascular spasms; - other disturbances in peripheral circulation, e.g. in limbs such as intermittent claudication and spasms, e.g. cholic; and - asthma, e.g. exertion-related asthma For the above-mentioned calcium-antagonistic uses an indicated daily dosage is from about 5 mg to about 500 mg suitably administered, e.g. orally, in divided doses of from about 1.25 mg to about 250 mg 2 to 4 times a day or in sustained release form.

In general the 2(S) optical isomers of the compounds relative to the propoxy side chain are more active than the 2(R) optical isomers as cardiotonic, antiarrhythmic and ss-adrenoceptor-blocking agents.

Preferred as p-adrenoceptor-blocking agents are compounds of the invention wherein in B the nitrogen atom attached to the propoxy side chain is part of a secondary amino group.

It will be appreciated that it may be necessary to convert a compound having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form to the corresponding unesterified compound prior to carrying out the in vitro tests indicated above for showing activity.

The cardiotonic use is the preferred use of the compounds.

The compounds may be administered in pharmaceutically acceptable salt form. Such salt forms exhibit the same order of activity as the free forms and are readily prepared in conventional manner.

The present invention also provides a pharmaceutical composition comprising a compound of the invention in free form or in pharma-ceutically acceptable salt form, in association with a pharmaceu-tical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet.

Claims

1. A compound of formula I

wherein V and W are hydrogen or together form an additional bond; and Ri is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or phenyl monosubstituted or independently disubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35;

wherein Rj is hydrogen or alkyl of 1 to 4 carbon atoms;

wherein n is 2, 3 or 4, Rk is hydrogen or alkyl of 1 to 4 carbon atoms and R, has the significances indicated above for Rj; and

wherein p is O or I; and R is alkyl independently disubstituted by aromatic, heteroaromatic and/or cycloaliphatic groups; with the proviso that when a) Ar is a group of formula A

wherein either R' is: hydrogen, methyl, hydroxymethyl, carboxyl, alkoxycarbonyl of altogether 2 to 5 carbon atoms, carbamoyl or cyano and R" is: hydrogen or methyl; or R' is: hydroxy and R" is: hydrogen; and additionally b) either p is 1 and B is: -a group i') of formula

wherein R, is gs defined above and V' and W' are hydrogen or, when R' is hydroxy and R" is hydrogen, V' and W' are hydrogen or together form an additional bond; or -a group ii) or iii) as defined above; or p is O or 1 and B is: a group iv') of formula

then R is other than diphenylalkyl of 13 to 17 carbon atoms or diphenylalkyl of 13 to 17 carbon atoms mono- or independently disubstituted in any of the phenyl rings by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35; and physiologically hydrolyzable derivatives thereof having the hydroxy group in the 2 position of the propoxy side chain in esterified form; in free form or in physiologically acceptable salt form.

2. A compound of claim 1 of formula la

wherein Ar, is:-phenyl; phenyl monosubstituted by hydroxy, benzyloxy, carboxy, alkoxycarbonyl of altogether 2 to 5 carbon atoms, trifluoromethyl, acetylmethyl, methylsulfonylamino, cyanomethylamino, amino, acetamido, (1 -hydroxymethylcyclohexyl)methyl, (1 -acetoxymethylcyclohexyl)methyl, 1 -dimethyla mino-3-oxo- 1-buten-2-yl or 3-cyano-1, 2-di hyd ro-6-methyl-2-oxopyridi n-5-yi; or phenyl disubstituted by: either nitro, amino, hydroxy or benzyloxy; or hydroxy and cyano; or benzyloxy and cyano; or acetyl and [2-methoxy]ethoxy; or cyano and [2 methoxyjethoxy; or nitro and methyl; - indolyl; indolyl monosubstituted in the 2-position by methyl, hydroxymethyl, carboxyl, alkoxycarbonyl of altogether 2 to 5 carbon atoms, carbamoyl, cyano or acetyl; indolyl monosubstituted in the 3-position by methyl or cyano; indolyl monosubstituted in the 6-position by carboxyl or alkoxycarbonyl of altogether 2 to 5 carbon atoms; indolyl monosubstituted in the 7-position by fluorine or alkoxyalkyl of 1 to 4 carbon atoms in each of the alkyl and alkoxy moieties thereof; indolyl disubstituted, in the 1-position by alkyl of 1 to 4 carbon atoms, alkoxycarbonyl of altogether 2 to 5 carbon atoms or alkoxy-carbonylalkyl of altogether 3 to 9 carbon atoms and in the 2-position by cyano, or in the 2- and 3-positions by cyano, or in the 2-position by methyl, hydroxymethyl, carboxyl, alkoxycarbonyl of altogether 2 to 5 carbon atoms, carbamovl or cyano and in the 3-position by methyl, or in the 2-position by cyano and in the 3-position by dimethylaminomethyl; - oxindolyl or oxindolyl substituted in the 3-position by two methyl groups; -2,1 ,3-benzoxadiazol-4-yl; - benzimidazol-4-yl or 2-trifluoromethylbenzimidazol-4-yl; -1 ,2-dihydro-2-oxobenzimidazol-4-yl; -[chinolin-2(1 H)-on]-4-yl or [3,4-dihyd rochinolin-2(1 H)-on]-4-yI;; -1-[9H]-carbazol-4-yl; -(spiro[cyclohexan-l ,2'-indan]-l'-onj-4'-yl; B and p are as defined in claim 1; and R, is alkyl of 1 to 5 carbon atoms which is independently di-substituted by: phenyl; phenyl mono- or independently di-substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen of atomic number of from 9 to 35, hydroxy, cyano, trifluoromethyl, nitro, amino, alkanoylamino of 2 to 5 carbon atoms or trifluoromethyl; pyridinyl; thienyl; furyl; pyrrolyl; imidazolyl; imidazolyl monosubstituted in the 1-position by methyl; or cycloalkyl of 3 to 7 carbon atoms; with the proviso that when a) Ar, is a group of formula A as defined in part a) of the proviso under formula I in claim 1 and additionally b) p and B are as defined in part b) of the proviso under formula I in claim 1, then R, is other than diphenylalkyl of 13 of 17 carbon atoms or diphenylalkyl of 13 to 17 carbon atoms mono- or inde-pendently disubstituted in any of the phenyl rings by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35; and their corresponding physiologically hydrolyzable derivatives; in free form or in physiologically acceptable salt form.

3. A compound of claim 1 of formula laa

wherein either R, is: hydrogen, methyl, hydroxymethyl, carboxyl, alkoxycarbonyl of altogether 2 to 5 carbon atoms, carbamoyl or cyano; and R2 is: hydrogen or methyl or R, is: hydroxy and R2 is: hydrogen; B and p are as defined in claim 1 and R, is as defined in claim 2; with the proviso that when B and pare as defined under part b) of the proviso under formula I in claim 1, then R, is other than diphenylalkyl of 13 to 17 carbon atoms or diphenylalkyl of 13 to 17 carbon atoms mono- or independently disubstituted in any of the phenyl rings by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35; and their corresponding physiologically hydrolyzable derivatives; in free form or in pharmaceutically acceptable salt form.

4. A compound of claim 1 of formula Ip

wherein R,p is: hydrogen, methyl hydroxymethyl, carboxyl, alkoxycarbonyl of altogether 2 to 5 carbon atoms, carbamoyl or cyano; R2p is: hydrogen or methyl either pp is 1 and Bp is: - a group p) of formula

wherein Rj is as defined in claim 1; or - a group ii) or iii) as defined in claim 1; or pp is O or 1 and Bp is: a group ivp) of formula

Rp is: alkyl independently disubstituted by aromatic, heteroaromatic and/or cycloalkyl groups; with the proviso that Rp is other than diphenylalkyl of 13 to 17 carbon atoms or diphenylalkyl of 13 to 17 carbon atoms mono- or independently disubstituted in any of the phenyl rings by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35; and their corresponding physiologically hydrolyzable derivatives; in free form or in physiologically acceptable salt form.

5. A compound of claim 1 of formula Ip'

wherein Rip, R2p and Rp are as defined in claim 4; and their corresponding physiologically hydrolyzable derivatives; in free form or in physiologically acceptable salt form.

6. A compound of claim 1 wherein Ar is 2-cyano-1H-indol-4-yl.

7. A compound of claim 1 in racemic form.

8. A compound of claim 1 in enantiomer form.

9. A compound of claim 1 in S-enantiomer form as regards the hydroxy-substituted carbon atom of the propoxy side chain.

10. A compound according to any one of claims 1 to 9 in free form.

11. A compound according to any one of claims 1 to 9 in neutral form.

12. A compound according to any one of claims 1 to 9 in salt form.

13. A compound according to any one of claims 1 to 9 in acid addition salt form.

14. A compound according to any one of claims 1 to 9 in free form or in pharmaceutically acceptable salt form, for use as a pharmaceutical.

15. A compound of claim 14 for use as a cardiotonic agent.

16. A compound of claim 14 for use as a calcium antagonist.

17. A compound of claim 14 for use as an antihypertensive.

18. A process for the production of a compound of claim 1 which includes the step of appropriately 3amino-2-oxypropylating a corresponding compound of formula IV

wherein Ar is as defined in claim 1, or a precursor form thereof.

19. A process for the production of a compound of claim 1 which comprises reacting a corresponding compound of formula II

wherein Ar is as defined in claim 1 and R, is a group capable of reacting with a primary or secondary amine to give a 2-amino-1-hydroxyethyl group, with a corresponding compound of formula Ill H-(CO)p-R III wherein p and R are as defined in claim 1 and where required appropriately esterifying the 2 position of the 3-aminopropoxy side chain in the resulting compound of formula I.

20. A pharmaceutical composition comprising a compound of claim 1 in free form or in pharmaceutically acceptable salt form in association with a pharmaceutical carrier or diluent

21. A method of preventing or treating heart insufficiency, heart rhythm disorders, disorders relating to a paralysis of intestine motility, Angina pectoris, conditions resulting from sympathetic overstimulation, hypertension, myocardial infarct, migraine, glaucoma, thyreotoxicosis, coronary insufficiency, disturbances in cerebral and peripheral circulation or asthma which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1 in free form or in pharmaceutically acceptable salt form.

22. A compound of claim 1 substantially as hereinbefore described with reference to any one of the Examples.